Taxol was first isolated from the stem bark of Western Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure (with the 2'- and 7- positions indicated) ##STR5## In ongoing clinical trials sponsored by the National Cancer Institute (NCI), taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers. A recent review article in the Journal of National Cancer Institute provides an overview on its mechanism of action, toxicology, clinical results, etc. E. Rowinsky et al., Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: 1247-1259 (1990).
One serious problem associated with taxol is that the compound is only very slightly soluble in water and this low solubility has created significant problems in developing suitable pharmaceutical formulations useful for human therapy. Some formulations for i.v. infusion have been developed which primarily utilize cremophore EL(R) as the drug carrier to overcome low water solubility problems. Cremophore, however, is itself somewhat toxic which could cause idiosyncratic histamine release and anaphylactoid like response. Thus, any improvement to increase water solubility by chemical modification is highly desired.
In some instances, taxol has been made more water soluble through the derivatization of the 2'- and/or 7-hydroxy group with a hydrophilic group resulting in a bioreversible form known as a prodrug. Prodrugs have been shown to improve physicochemical (e.g. solubility, lipophilicity, etc.) and biological properties of many compounds. One approach to form a water soluble prodrug of a hydroxy containing molecule has been to derivatize the hydroxy group into an N-substituted-(aminomethyl)benzoate ester. See for example, Bundgaard et al., J. Med. Chem., 32, pp 2507-2509 (1989); Jensen et al., International Journal of Pharmaceutics, 58, pp 143-153 (1990); U.S. Pat. No. 4,623,486, issued to Lombardino on Nov. 18, 1986.
We have now discovered that certain 2'-N-substituted-aminomethylbenzoate or 2'-N-substituted-aminobenzoate taxol derivatives, optionally substituted with a (phosphonooxyphenyl)alkanoyloxy, (phosphonooxy)alkanoyloxy, or [(phosphonooxyalkyl)phenyl]alkanoyloxy group on the (C)7-position of taxol, have respectable water solubility and good anti-tumor activities. Thus, it is the intention of this invention to provide novel 2'-N-substituted-aminomethylbenzoate or 2'-N-substututed-aminobenzoate taxol derivatives, with or without the 7-O-(phosphonooxyphenyl)alkanoyl, (phosphonooxy)alkanoyl, or [(phosphonooxyalkyl)phenyl]alkanoyl group, which are useful in treating mammalian tumors.